CN102659593B - 紫草宁苯氧羧酸酯类衍生物及其合成方法和应用 - Google Patents
紫草宁苯氧羧酸酯类衍生物及其合成方法和应用 Download PDFInfo
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Abstract
本发明属于化学制药技术领域,具体涉及一种紫草宁苯氧羧酸酯类衍生物的制备及其在肿瘤抑制方面的应用。通过合成手段将苯氧基羧酸类药物中间体引入到紫草宁骨架分子中获得相应酯类衍生物,体外抗肿瘤活性研究表明,苯氧羧酸紫草宁衍生物对肿瘤细胞株有很强的抑制活性。
Description
一:技术领域
本发明属于化学制药技术领域,具体涉及一种紫草宁苯氧羧酸酯类衍生物的制备及其在肿瘤抑制方面的应用。
二:背景技术
紫草宁具有杀菌、消炎、抗氧化及肿瘤抑制活性。近年来研究表明,它作为先导物在抑制肿瘤活性的功能分子研究方面具有很大潜力。但是,在后续研究中发现紫草宁存在溶解性、细胞毒性等缺点。
Yang Fan等于2006年在《International Journal of Cancer》第119期第1184-1193页发表的SH-7,A New Synthesized Shikonin Derivative,Exerting Its Potent Anti-tumor Activities as aTopoisomerase Inhibitor(SH-7,一个新的合成得到的紫草宁衍生物,作为拓扑异构酶发挥其有效的抗癌活性)文章表明,以紫草宁骨架进行修饰的紫草宁衍生物对拓扑异构酶的抑制作用明显强于紫草宁,同时该衍生物能够抑制体外培养的肿瘤细胞S-180,SMMC-7721,BEL-7402以及PC-3四株癌细胞的生长,这一结果显示出了紫草宁酯类衍生物在肿瘤抑制方面具有很好的活性,可作进一步的研究。陆群等制备了系列紫草宁衍生物(一类萘茜衍生物及其制备方法和用途,CN 1199931),经药理实验证实,该类化合物可作为端粒酶抑制剂而发挥其功能,该系列化合物可有效抑制端粒酶的活性,进而抑制肿瘤细胞生长和增殖,在肿瘤药物开发方面有很好的前景,其中SH-12为苯氧乙酰基紫草宁酯类衍生物。
Stoner E.J.等人于1999年在《Organic Process Research & Development》第3期第145-148页发表的Synthesis of ABT-378,an HIV Protease Inhibitor andidate:Avoiding the Use ofCarbodiimides in a Difficult Peptide Coupling (洛匹那韦的合成,一种抗HIV蛋白酶抑制剂的潜在药物:避免使用多肽偶联条件下的碳二亚胺)文章表明,通过对第一代抗蛋白酶抑制剂有效药物利托那韦的定向改造(将利托那韦左侧链的噻唑乙酸换成2,6-二甲基苯氧乙酸),成功获得了新一代抗HIV潜力巨大的明星药物洛匹那韦。2002年,Sham H.L.等人在《Bioorganic& Medicinal Chemistry Letters》第12期第3101-3103页发表的文章验证了洛匹那韦对HIV蛋白酶的抑制率和在MT-4细胞中的抗病毒活性。其中,对于HIV蛋白酶的抑制率达到了93%;抗病毒EC50值达到了0.10uM,细胞毒性IC50值达到了17.8uM。正是苯氧羧酸结构在药物中发挥着重要的功能,因此,我们将含有苯氧羧酸的结构分子引入到紫草宁的支链羟基上,并通过肿瘤细胞活性验证该类功能分子具有显著的肿瘤细胞抑制活性。
三:发明内容
本发明以紫草宁为起始原料,通过半合成获得一类新颖苯氧羧酸紫草宁酯类衍生物。抗肿瘤活性表明,该类衍生物对肿瘤细胞株A875、HepG2、HeLa具有明显的抑制活性,其中在A875细胞活性结果中,2-苯氧丁酸紫草宁酯活性最优,IC50值达到了0.963μmol/mL;在HepG2细胞活性结果中,3-甲基苯氧乙酸紫草宁酯活性最好,IC50值达到了0.282μmol/mL;在HeLa细胞活性结果中,4-苯氧基苯乙酸紫草宁酯活性最佳,IC50值达到了4.314μmol/mL
本发明需要解决的问题是提供一类紫草宁苯氧羧酸酯类衍生物及其制备方法和在肿瘤抑制中的应用。
本发明的紫草宁酯类衍生物结构通式如式I所示:
式I中的R1所代表的基团分别为下列各项之一:
(1)、式I中R1为苯氧乙酸基;
(2)、式I中R1为3-氯苯氧乙酸基;
(3)、式I中R1为4-异丙基苯氧乙酸基;
(4)、式I中R1为2,5-二甲基苯氧乙酸基;
(5)、式I中R1为邻氯苯氧乙酸基;
(6)、式I中R1为对氟苯氧乙酸基;
(7)、式I中R1为对叔丁基苯氧乙酸基;
(8)、式I中R1为2-甲基-4-氯苯氧乙酸基;
(9)、式I中R1为对氯苯氧乙酸基
(10)、式I中R1为2-苯氧基丁酸基
(11)、式I中R1为间甲基苯氧乙酸基
(12)、式I中R1为2-(4-氯苯氧基)异丁酸基
(13)、式I中R1为对溴苯氧乙酸基
(14)、式I中R1为2,3-二甲基苯氧乙酸基
(15)、式I中R1为4-(4-氯-2-甲基苯氧基)丁酸基
(16)、式I中R1为2,6-二甲基苯氧乙酸基
(17)、式I中R1为3-苯氧基苯乙酸基
(18)、式I中R1为4-苯氧基苯乙酸基
(19)、式I中R1为4-苯氧丁酸基
(20)、式I中R1为3-苯氧丙酸基
(21)、式I中R1为2-苯氧丙酸基
(22)、式I中R1为4-甲基苯氧乙酸基
本发明的式I结构紫草宁苯氧基羧酸酯类衍生物是通过紫草宁与相应羧酸半合成得到的新颖结构功能化合物。
本发明通过体外肿瘤细胞抑制活性证明紫草宁苯氧羧酸酯类衍生物对A875、HepG2、HeLa具有明显的抑制活性,其中它们的最优化合物生物活的IC50值分别达到了0.963μmol/mL、0.282μmol/mL、4.314μmol/mL。
紫草宁具有杀菌、抗肿瘤等活性,在已有发表的文献中,紫草宁的体外肿瘤细胞抑制活性在微摩尔级,更多的研究希望能够将这一数量级降低,进而更有效地达到抑制肿瘤的目的。本发明所述紫草宁苯氧基羧酸酯类衍生物在与紫草宁相比较过程中优势明显,其中在A875细胞活性结果中,2-苯氧丁酸紫草宁酯活性最优,IC50值达到了0.963μmol/mL;在HepG2细胞活性结果中,3-甲基苯氧乙酸紫草宁酯活性最好,IC50值达到了0.282μmol/mL;在HeLa细胞活性结果中,4-苯氧基苯乙酸紫草宁酯活性最佳,IC50值达到了4.314μmol/mL,可制备成抗肿瘤药物。
四:附图说明
图1表示紫草宁苯氧基羧酸酯类衍生物对肿瘤细胞A875的体外活性。
图2表示紫草宁苯氧基羧酸酯类衍生物对肿瘤细胞HepG2的体外活性。
图3表示紫草宁苯氧基羧酸酯类衍生物对肿瘤细胞HeLa的体外活性。
五:具体实施方式
实例一:式I类紫草宁衍生物的合成方法
取50mmol紫草宁和50mmol相应羧酸溶解在20mL无水二氯甲烷中,于-10℃~0℃继续加入催化剂量的N,N-二环己基碳二亚胺(DCC)和4-二甲氨基吡啶(DMAP),TLC跟踪检测生成紫草宁酯类衍生物。加入硅胶减压浓缩溶剂,以乙酸乙酯∶石油醚=1∶7柱层析,得紫草宁羧酸酯类衍生物。
反应以苯氧乙酸为例:
同法可以得到化合物2~21。
相应化合物的理化数据如下:
化合物1 Red powder,yield 48.4%.Mp:109.2-111.6℃.1H NMR(500MHz,CDCl3)δ:12.57(s,1H,-OH),12.41(s,1H,-OH),7.31(t,J=7.7Hz,2H,Ar-H),7.18(s,2H,naphthoquinone-H),7.01(t,J=7.4Hz,1H,Ar-H),6.92(s,2H,Ar-H),6.90(s,1H,naphthoquinone-H),6.16(dd,J1=7.3,J2=4.6Hz,1H,-O-CH),5.04(t,J=7.2Hz,1H,-CH=C),4.72(s,2H,-CH2-O),2.67-2.60(m,1H,-C-CH2-C=C),2.52-2.46(m,1H,-C-CH2-C=C),1.67(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C24H22O7:445.1258,found:445.1270.
化合物2 Red powder,yield 69.9%.Mp:96.3-98.5℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.40(s,1H,-OH),7.23(dd,J1=13.4,J2=5.3Hz,1H,Ar-H),7.18(s,2H,naphthoquinone-H),7.00(dd,J1=5.4,J2=4.4Hz,1H,Ar-H),6.94(s,1H,naphthoquinone-H)6.92(dd,J1=7.7,J2=5.6Hz,1H,Ar-H),6.80(dd,J1=8.4,J2=2.5Hz,1H,Ar-H),6.17(dd,J1=7.2,J2=4.6Hz,1H,-O-CH),5.04(t,J=7.2Hz,1H,-CH=C),4.70(s,2H,-CH2-O),2.68-2.62(m,1H,-C-CH2-C=C),2.53-2.47(m,1H,-C-CH2-C=C),1.68(s,3H,C=C-CH3),1.57(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C24H21ClO7:479.0868,found:479.0868.
化合物3 Red powder,yield 54.1%.Mp:97.3-99.6℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.41(s,1H,-OH),7.18(s,2H,naphthoquinone-H),7.15(d,J=8.5Hz,2H,Ar-H),6.93(s,1H,naphthoquinone-H),6.84(d,J=8.6Hz,2H,Ar-H),6.14(dd,J1=6.7,J2=4.8Hz,1H,-O-CH),5.11(t,J=7.1Hz,1H,-CH=C),4.69(s,2H,-CH2-O),2.86(dt,J1=13.8,J2=6.9Hz,1H,Ar-CH),2.66-2.59(m,1H,-C-CH2-C=C),2.52-2.46(m,1H,-C-CH2-C=C),1.67(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3),1.22(s,3H,Ar-C-CH3),1.21(s,3H,Ar-C-CH3).ESI-MS:calcd.for[M+Na]+ofC27H28O7:487.1727,found:487.1728.
化合物4 Red powder,yield 63.4%.Mp:89.5-91.6℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.41(s,1H,-OH),7.18(s,2H,naphthoquinone-H),7.05(d,J=7.5Hz,1H,Ar-H),6.89(s,1H,naphthoquinone-H),6.73(d,J=7.3Hz,1H,Ar-H),6.51(s,1H,Ar-H),6.14(dd,J1=6.7,J2=4.8Hz,1H,-O-CH),5.05(t,J=7.3Hz,1H,-CH=C),4.72(s,2H,-CH2-O),2.66-2.60(m,1H,-C-CH2-C=C),2.52-2.46(m,1H,-C-CH2-C=C),2.29(s,3H,Ar-H),2.26(s,3H,Ar-H),1.66(s,3H,1C=C-CH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C26H26O7:473.1571,found:473.1563.
化合物5 Red powder,yield 70.5%.Mp:108.1-110.4℃.1H NMR(500MHz,CDCl3)δ:12.57(s,1H,-OH),12.41(s,1H,-OH),7.41(dd,J=7.9,1.5Hz,1H,Ar-H),7.21(dd,J=6.3,2.8Hz,1H,Ar-H),7.18(s,2H,naphthoquinone-H),6.99-6.96(m,1H,Ar-H),6.95(s,1H,naphthoquinone-H),6.84(d,J=8.2Hz,1H,Ar-H),6.16(dd,J1=6.8,J2=4.7Hz,1H,-O-CH),5.04(t,J=7.3Hz,1H,-CH=C),4.80(s,2H,-CH2-O),2.68-2.59(m,1H,-C-CH2-C=C),2.53-2.47(m,1H,-C-CH2-C=C),1.66(s,3H,C=C-CH3),1.55(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+ofC24H21ClO7:479.0868,found:479.0825.
化合物6 Red powder,yield 53.3%.Mp:109.5-111.8℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.40(s,1H,-OH),7.18(s,2H,naphthoquinone-H),6.99(dd,J1=11.6,J2=5.6Hz,2H,Ar-H),6.92(s,1H,naphthoquinone-H),6.88-6.84(m,2H,Ar-H),6.16(dd,J1=7.0,J2=4.7Hz,1H,-O-CH),5.04(t,J=7.2Hz,1H,-CH=C),4.68(s,2H,-CH2-O),2.68-2.59(m,1H,-C-CH2-C=C),2.53-2.47(m,1H,-C-CH2-C=C),1.67(s,3H,C=C-CH3),1.57(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C24H21FO7:463.1164,found:463.1169.
化合物7 Red powder,yield 55.8%.Mp:111.0-113.5℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.41(s,1H,-OH),7.32-7.30(m,2H,Ar-H),7.18(s,2H,naphthoquinone-H),6.94(s,1H,naphthoquinone-H),6.85-6.83(m,2H,Ar-H),6.16(dd,J1=7.2,J2=4.6Hz,1H,-O-CH),5.05(t,J=7.3Hz,1H,-CH=C),4.69(s,2H,-CH2-O),2.66-2.61(m,1H,-C-CH2-C=C),2.53-2.48(m,1H,-C-CH2-C=C),1.67(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3),1.29(s,9H,-C(CH3)3).ESI-MS:calcd.for[M+Na]+of C28H30O7:501.1884,found:501.1875.
化合物8 Red powder,yield 55.5%.Mp:100.8-102.6℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.40(s,1H,-OH),7.18(s,2H,naphthoquinone-H),7.15(s,1H,Ar-H),7.08(d,J=8.7Hz,1H,Ar-H),6.92(s,1H,naphthoquinone-H),6.61(d,J=8.6Hz,1H,Ar-H),6.16-6.12(m,1H,-O-CH),5.04(t,J=6.7Hz,1H,-CH=C),4.71(s,2H,-CH2-O),2.67-2.59(m,1H,-C-CH2-C=C),2.52-2.46(m,1H,-C-CH2-C=C),2.28(s,3H,Ar-CH3),1.67(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C25H23ClO7:493.1025,found:493.1023.
化合物9 Red powder,yield 68.4%.Mp:109.4-112.2℃.1H NMR(500MHz,CDCl3)δ:12.62(s,1H,-OH),12.44(s,1H,-OH),7.30(s,2H,Ar-H),7.22(s,2H,naphthoquinone-H),6.98(s,1H,naphthoquinone-H),6.88(d,J=8.7Hz,2H,Ar-H),6.21-6.16(m,1H,-O-CH),5.07(t,J=6.7Hz,1H,-CH=C),4.73(s,2H,-CH2-O),2.71-2.64(m,1H,-C-CH2-C=C),2.57-2.51(m,1H,-C-CH2-C=C),1.72(s,3H,C=C-CH3),1.61(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+ofC24H21ClO7:479.0868,found:479.0887.
化合物10 Red powder,yield 61.2%.Mp:82.1-84.4℃.1H NMR(500MHz,CDCl3)δ:12.57(s,1H,-OH),12.42(s,1H,-OH),7.28(d,J=7.4Hz,2H,Ar-H),7.18(s,2H,naphthoquinone-H),7.02(s,1H,naphthoquinone-H),6.97(t,J=7.5Hz,1H,Ar-H),6.88(d,J=8.3Hz,2H,Ar-H),6.08-6.04(m,1H,-O-CH),4.86(t,J=7.0Hz,1H,-CH=C),4.65(t,J=6.1Hz,1H,OOCCH-),2.57-2.53(m,1H,-C-CH2-C=C),2.45-2.38(m,1H,-C-CH2-C=C),2.02-1.99(m,2H,Ar-OCH),1.57(s,3H,C=C-CH3),1.50(s,3H,C=C-CH3),1.12(d,J=7.4Hz,3H,-CCH3).ESI-MS:calcd.for[M+Na]+of C26H26O7:473.1571,found:473.1568.
化合物11 Red powder,yield 62.9%.Mp:101.8-103.6℃.1H NMR(500MHz,CDCl3)δ12.62(s,1H,-OH),12.45(s,1H,-OH),7.31(s,1H,Ar-H),7.22(s,2H,naphthoquinone-H),6.96(s,1H,naphthoquinone-H),6.87(d,J=7.5Hz,1H,Ar-H),6.78(s,1H,Ar-H),6.74(d,J=8.1Hz,1H,Ar-H),6.21-6.17(m,1H,-O-CH),5.09(t,J=6.7Hz,1H,-CH=C),4.74(s,2H,-CH2-O),2.71-2.64(m,1H,-C-CH2-C=C),2.54(m,1H,-C-CH2-C=C),2.37(s,3H,Ar-CH3),1.71(s,3H,C=C-CH3),1.61(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C25H24O7:459.1414,found:459.1417.
化合物12 Red oil liquid,yield 59.8%.1H NMR(500MHz,CDCl3)δ:12.59(s,1H,-OH),12.39(s,1H,-OH),7.18(s,2H,naphthoquinone-H),7.15(d,J=8.5Hz,2H,Ar-H),6.83(s,1H,naphthoquinone-H),6.75(d,J=8.5Hz,2H,Ar-H),6.08(dd,J1=7.7,J2=4.6Hz,1H,-O-CH),4.99(t,J=6.7Hz,1H,-CH=C),2.60-2.53(m,1H,-C-CH2-C=C),2.50-2.44(m,1H,-C-CH2-C=C),1.64(s,3H,-CCH3),1.62(s,3H,C=C-CH3),1.61(s,3H,-CCH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C26H25ClO7:507.1181,found:507.1188.
化合物13 Red powder,yield 51.5%.Mp:107.4-110.8℃.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.40(s,1H,-OH),7.39(d,J=8.5Hz,2H,Ar-H),7.18(s,2H,naphthoquinone-H),6.93(s,1H,naphthoquinone-H),6.79(d,J=8.5Hz,2H,Ar-H),6.15(dd,J1=7.2,J2=4.6Hz,1H,-O-CH),5.03(t,J=7.0Hz,1H,-CH=C),4.68(s,2H,-CH2-O),2.67-2.59(m,1H,-C-CH2-C=C),2.52-2.46(m,1H,-C-CH2-C=C),1.67(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C24H21BrO7:523.0363,found:523.0348.
化合物14 Red powder,yield 47.4%.Mp:117.0-119.2℃.1H NMR(500MHz,CDCl3)δ:12.57(s,1H,-OH),12.41(s,1H,-OH),7.18(s,2H,naphthoquinone-H),7.02(dd,J1=9.7,J2=6.1Hz,1H,Ar-H),6.92(s,1H,naphthoquinone-H),6.83(d,J=7.6Hz,1H),6.63-6.57(m,1H,Ar-H),6.15(dd,J1=6.7,J2=4.9Hz,1H,-O-CH),5.05(t,J=7.3Hz,1H,-CH=C),4.71(s,2H,-CH2-O),2.67-2.60(m,1H,-C-CH2-C=C),2.52-2.46(m,1H,-C-CH2-C=C),2.28(s,3H,Ar-CH3),2.23(s,3H,Ar-CH3),1.67(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C26H26O7:473.1571,found:473.1569.
化合物15 Red powder,yield 68.8%.Mp:81.1-83.8℃.1H NMR(500MHz,CDCl3)δ:12.59(s,1H,-OH),12.41(s,1H,-OH),7.18(s,2H,naphthoquinone-H),7.07(d,J=8.4Hz,2H,Ar-H),6.98(s,1H,naphthoquinone-H),6.68(d,J=8.2Hz,1H,Ar-H),6.08-6.04(m,1H,-O-CH),5.10(t,J=6.8Hz,1H,-CH=C),3.98(t,J=5.9Hz,2H,-CH2-O),2.68-2.61(m,2H,-OOCCH2),2.60-2.57(m,1H,-C-CH2-C=C),2.51-2.45(m,1H,-C-CH2-C=C),2.18(s,3H,Ar-CH3),2.17-2.12(m,2H,-OOCCCH2),1.66(s,3H,C=C-CH3),1.56(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+ofC27H27ClO7:521.1338,found:521.1330.
化合物16 Red powder,yield 84.6%.Mp:100.4-102.1℃.1H NMR(500MHz,CDCl3)δ:12.60(s,1H,-OH),12.42(s,1H,-OH),7.19(s,2H,naphthoquinone-H),7.04(d,J=6.8Hz,2H,Ar-H),7.01(s,1H,naphthoquinone-H),6.98-6.94(m,1H,Ar-H),6.24-6.19(m,1H,-O-CH),5.14(t,J=7.0Hz,1H,-CH=C),4.49(s,2H,-CH2-O),2.73-2.64(m,1H,-C-CH2-C=C),2.57-2.51(m,1H,-C-CH2-C=C),2.31(s,6H,Ar-(CH3)2),1.69(s,3H,C=C-CH3),1.59(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C26H26O7:473.1571,found:473.1576.
化合物17 Red oil liquid,yield 82.4%.1H NMR(500MHz,CDCl3)δ:12.56(s,1H,-OH),12.41(s,1H,-OH),7.35-7.28(m,3H,Ar-H),7.17(s,2H,naphthoquinone-H),7.10(t,J=7.4Hz,1H,Ar-H),7.02(d,J=8.4Hz,3H,Ar-H),6.95-6.93(m,2H,Ar-H),6.79(s,1H,naphthoquinone-H),6.02(dd,J1=7.2,J2=4.5Hz,1H,-O-CH),5.04(t,J=6.8Hz,1H,-CH=C),3.66(s,2H,Ar-CH2),2.63-2.54(m,1H,-C-CH2-C=C),2.46-2.40(m,1H,-C-CH2-C=C),1.65(s,3H,C=C-CH3),1.54(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C26H26O7:521.1571,found:521.1561.
化合物18 Red oil liquid,yield 78.8%.1H NMR(500MHz,CDCl3)δ:12.56(s,1H,-OH),12.41(s,1H,-OH),7.34(t,J=7.4Hz,2H,Ar-H),7.26(s,2H,Ar-H),7.17(s,2H,naphthoquinone-H),7.11(t,J=7.3Hz,1H,Ar-H),7.03(d,J=8.3Hz,2H,Ar-H),6.99(d,J=7.8Hz,2H,Ar-H),6.79(s,1H,naphthoquinone-H),6.03(dd,J1=7.2,J1=4.5Hz,1H,-O-CH),5.06(t,J=6.8Hz,1H,-CH=C),3.67(s,2H,Ar-CH2),2.65-2.56(m,1H,-C-CH2-C=C),2.45(m,1H,-C-CH2-C=C),1.67(s,3H,C=C-CH3),1.55(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C26H26O7:521.1571,found:521.1577.
化合物19 Red oil liquid,yield 81.8%.1H NMR(500MHz,CDCl3)δ:12.59(s,1H,-OH),12.42(s,1H,-OH),7.26(s,2H,Ar-H),7.18(s,2H,naphthoquinone-H),6.99(s,1H,naphthoquinone-H),6.93(t,J=7.6Hz,1H,Ar-H),6.88(d,J=8.5Hz,2H,Ar-H),6.08-6.03(m,1H,-O-CH),5.11(t,J=7.0Hz,1H,-CH=C),4.01(t,J=5.9Hz,2H,-OOCCH2),2.64(dd,J1=15.3,J2=8.1Hz,2H,Ar-OCH2),2.60-2.57(m,1H,-C-CH2-C=C),2.51-2.45(m,1H,-C-CH2-C=C),2.16-2.08(m,2H,Ar-OCCH2),1.66(s,3H,C=C-CH3),1.57(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+ofC26H26O7:473.1571,found:473.1567.
化合物20 Red oil liquid,yield 83.6%.1H NMR(500MHz,CDCl3)δ:12.58(s,1H,-OH),12.43(s,1H,-OH),7.30(s,1H,Ar-H),7.27-7.25(m,1H,Ar-H),7.17(s,2H,naphthoquinone-H),7.05(s,1H,naphthoquinone-H),6.98-6.89(m,3H,Ar-H),6.07(dd,J1=7.1,J2=4.5Hz,1H,-O-CH),5.11(t,J=6.7Hz,1H,-CH=C),4.29-4.26(m,2H,-OOCCH2),2.88(t,J=6.1Hz,2H,Ar-OCH2),2.68-2.59(m,1H,-C-CH2-C=C),2.51-2.45(m,1H,-C-CH2-C=C),1.65(s,3H,C=C-CH3),1.57(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C25H24O7:459.1414,found:459.1412.
化合物21 Red oil liquid,yield 84.8%.1H NMR(500MHz,CDCl3)δ:12.57(s,1H,-OH),12.42(s,1H,-OH),7.27(d,J=6.3Hz,2H,Ar-H),7.17(s,2H,naphthoquinone-H),7.03(s,1H,naphthoquinone-H),6.97(t,J=7.5Hz,1H,Ar-H),6.88(d,J=7.8Hz,2H,Ar-H),6.06(dd,J1=7.6,J2=4.5Hz,1H,-O-CH),5.11(t,J=7.0Hz,1H,-CH=C),4.86-4.82(m,1H,Ar-OCH),2.61-2.51(m,1H,-C-CH2-C=C),2.46-2.37(m,1H,-C-CH2-C=C),1.66(d,J=6.8Hz,3H,-CCH3),1.58(s,3H,C=C-CH3),1.51(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C25H24O7:459.1414,found:459.1409.
化合物22 Red oil liquid,yield 66.7%.1H NMR(500MHz,CDCl3)δ12.59(s,1H,-OH),12.43(s,1H,-OH),7.20(s,2H,naphthoquinone-H),7.11(d,J=8.6Hz,2H,Ar-H),6.92(s,1H,naphthoquinone-H),6.83(d,J=8.4Hz,2H,Ar-H),6.17(dd,J1=7.2,J2=4.6Hz,1H,-O-CH),5.06(t,J=7.1Hz,1H,-CH=C),4.71(s,2H,-CH2-O),2.69-2.61(m,1H,-C-CH2-C=C),2.54-2.48(m,1H,-C-CH2-C=C),2.31(s,3H,Ar-CH3),1.69(s,3H,C=C-CH3),1.59(s,3H,C=C-CH3).ESI-MS:calcd.for[M+Na]+of C25H24O7:459.1414,found:459.1415.
实例三.式I类紫草宁苯氧基羧酸衍生物应用
我们对式I类紫草宁苯氧羧酸衍生物进行了抗肿瘤活性研究,选取肿瘤细胞A875、HepG2、HeLa为检测细胞,以MTT法,酶标仪于570nm条件下测定其吸光度并计算OD值。
IC50值计算方法如式所示:
细胞抑制率(%)=(对照组OD值-实验组OD值)/对照组OD值×100%
结果表明,紫草宁酯类衍生物在抗肿瘤活性方面具有一定的潜力。相应结果见附图1。
细胞活性结果表明,化合物10、11、18的活性明显优于其它酯类衍生物,分别对A875、HepG2、HeLa细胞株的IC50值为0.963μmol/mL、0.282μmol/mL、4.314μmol/mL。
本发明所述紫草宁苯氧羧酸酯类衍生物可制备成抗肿瘤药物。
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